Fungotill liposomal

Package leaflet: Information for the user

Fungotill Liposomal 50 mg powder for concentrate for dispersion for infusion

Amphotericin B
Equivalent medicine
Please read all of this leaflet carefully before you are given this medicine as it contains important information for you

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• If you get any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet

1. What Fungotill Liposomal is and what it is used for
2. What you need to know before you are given Fungotill Liposomal
3. How to use Fungotill Liposomal
4. Possible side effects
5. How to store Fungotill Liposomal
6. Contents of the pack and other information

1. What Fungotill Liposomal is and what it is used for

What Fungotill Liposomal is
Fungotill Liposomal contains the active substance amphotericin B. Fungotill liposomal is an antifungal antibiotic, that is, a medicine used to treat serious fungal infections.
Fungotill Liposomal is used for:

• Treatment of serious systemic and/or deep fungal infections (mycoses);
• Empirical treatment of patients with low neutrophil counts (decreased number of white blood cells, neutropenia) who are suspected of having a fungal infection and who have fever.

Fungotill Liposomal can be used as a secondary therapy for visceral leishmaniasis ( Leishmania donovani ) in immunocompetent patients and in patients with compromised immune systems (e.g., people affected by HIV). In patients with compromised immune systems, relapses may be expected. There is no experience regarding the prevention of relapses.

2. What you need to know before using Fungotill Liposomal

Do not use Fungotill Liposomal

• if you are allergic to amphotericin B or to any of the other components of Fungotill Liposomal listed in section 6.
• Fungotill Liposomal contains soybean oil. If you are allergic to peanuts or soybeans, do not use this medicine.

Warnings and precautions
Talk to your doctor or pharmacist before using Fungotill Liposomal.
Pay special attention when using Fungotill Liposomal:

• If you experience a severe allergic (anaphylactic) reaction. In this case, your doctor will stop the infusion;
• If you develop other infusion-related reactions. In this case, your doctor may slow down the infusion, administering Fungotill Liposomal over a longer period of time (approximately 2 hours). Your doctor may also administer medicines to prevent or treat infusion-related reactions, such as diphenhydramine (an antihistamine), paracetamol, meperidine (to relieve pain), and/or hydrocortisone (an anti-inflammatory medicine that works by reducing the immune system's response);
• If you are taking other medicines that may cause kidney damage, see the section Other medicines and Fungotill Liposomal. Fungotill Liposomal may cause kidney damage. Your doctor or nurse will take blood samples to measure creatinine (a chemical in the blood that reflects kidney function) and levels of electrolytes (particularly potassium and magnesium) before and during treatment with Fungotill Liposomal, as both may become abnormal if kidney function is impaired. This is especially important if you have previously had kidney damage or if you are taking other medicines that may affect kidney function. Blood samples will also be analyzed to check for possible changes in liver function and the body's ability to produce new blood cells and platelets;
• If blood tests show changes in kidney function or other significant changes, your doctor may administer a lower dose of Fungotill Liposomal or discontinue treatment;
• If blood tests show low potassium levels. In this case, your doctor may prescribe a potassium supplement to be taken during treatment with Fungotill Liposomal;
• If blood tests show high potassium levels, you may experience irregular heartbeat, sometimes severe.
• If you receive a white blood cell transfusion. If you receive an infusion of Fungotill Liposomal during or immediately after a white blood cell transfusion, sudden and severe lung problems may occur. Your doctor will recommend that the infusions be separated by as long a time interval as possible. This will reduce the risk of lung problems, and your lungs will be monitored.

If any of the conditions listed above apply to you, your doctor may decide to modify your treatment.

Other medicines and Fungotill Liposomal
Tell your doctor if you are taking, have recently taken, or might take any other medicines, including those without a prescription.
The following medicines, known to interact with amphotericin B, may also interact with Fungotill Liposomal.

• Medicines that may cause kidney damage:
  • medicines that suppress the immune system (immunosuppressants), such as cyclosporine;
  • certain antibiotics called aminoglycosides (including gentamicin, neomycin, and streptomycin);
  • pentamidine, a medicine used to treat lung inflammation (pneumonia) in patients with AIDS or leishmaniasis.  Inform your doctor if you are taking any of these medicines. These medicines may cause kidney damage that Fungotill Liposomal could worsen. If you are taking any of these medicines, your doctor or nurse will regularly prescribe blood tests to monitor kidney function.
• Medicines that may lower potassium levels:
  • corticosteroids, anti-inflammatory medicines that work by reducing the immune system's response;
  • corticotropin (ACTH), used to regulate the body's natural production of corticosteroids in response to stress;
  • diuretics, medicines that increase the amount of urine produced by the body. Among these, furosemide;
  • digitalis glycosides, medicines derived from the foxglove plant (Digitalis purpurea) and used to treat heart failure. Fungotill Liposomal may reduce potassium levels in the blood, which in turn may worsen the side effects of digitalis (irregular heartbeat);
  • muscle relaxants, such as tubocurarine. Fungotill Liposomal may enhance the muscle-relaxing effect.  Inform your doctor if you are taking any of these medicines.

Other medicines:

• antifungal medicines (medicines used to treat fungal infections), such as flucytosine. Fungotill Liposomal may worsen the side effects of flucytosine. This includes changes in the body's ability to produce new blood cells. This may be observed in blood tests;
• certain anticancer medicines, such as methotrexate, doxorubicin, carmustine, and cyclophosphamide. Taking these medicines with Fungotill Liposomal may cause kidney damage, wheezing or difficulty breathing, and low blood pressure;
• white blood cell (leukocyte) transfusions. Sudden and severe lung problems may occur if you are given an infusion of Fungotill Liposomal during or immediately after a white blood cell transfusion. Your doctor will recommend that the infusions be separated by as long a time interval as possible. This will reduce the risk of lung problems, and your lungs will be monitored.  Inform your doctor if you are taking any of these medicines.

Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor before using this medicine.
The safety of using liposomal amphotericin B during pregnancy has not been established. If you are pregnant, your doctor will prescribe Fungotill Liposomal only if the expected benefit of treatment for you and your unborn child outweighs the potential risks.
It is not known whether liposomal amphotericin B passes into breast milk. The decision to breastfeed during treatment with Fungotill Liposomal should take into account the potential risk to the infant, the benefit of breastfeeding for the infant, and the benefit of Fungotill Liposomal therapy for the mother.

Driving and using machines
Some of the possible side effects of Fungotill Liposomal may affect your ability to drive or operate machinery. See section 4, Possible side effects.

Fungotill Liposomal contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per vial/dose, i.e., it is essentially "sodium-free".

3. How to use Fungotill Liposomal

Fungotill Liposomal is always administered by a doctor or nurse.
Liposomal amphotericin B is NOT interchangeable with non-liposomal amphotericin B formulations.
To prepare the infusion dispersion, Fungotill Liposomal must be dissolved in sterile water for
injection and then diluted with a glucose-containing solution. Administration is into a vein (intravenous use). Fungotill Liposomal must not be administered by any other route.
Fungotill Liposomal must not be mixed with saline solutions or with other medicines or electrolytes (see the section " The following information is intended exclusively for healthcare professionals " in the package leaflet).

Use in adults
The dose of Fungotill Liposomal will depend on your body weight and will be individually adjusted according to the patient's needs.
The medicine is for intravenous infusion after reconstitution and dilution.
Generally, the infusion time is 30–60 minutes. To reduce the risk of infusion-related adverse reactions, slower infusion rates (over 2 hours) may be considered, especially with higher daily doses.

Treatment of fungal infections:
Fungotill Liposomal is usually administered at a dose of 3 mg per kg of body weight per day. For the treatment of Aspergillus infections, the dose may be gradually increased to 5 mg/kg/day.
Mucormycosis: Fungotill liposomal is usually administered at a dose of 5–10 mg/kg/day.

Empirical treatment in suspected fungal infection:
Fungotill Liposomal is administered at a dose of 3 mg/kg/day.

Treatment of visceral leishmaniasis:
Your doctor will follow national and international therapeutic guidelines to determine the most appropriate dose and treatment schedule for you. Generally, the dose ranges between 3 and 5 mg/kg/day. The duration of treatment ranges from 10 to 38 days, depending on the chosen therapeutic regimen and the presence or absence of HIV co-infection.

Use in patients with kidney problems
It is not necessary to modify the dose or frequency of infusion. Your doctor or nurse will regularly take blood samples to monitor for any changes in kidney function during treatment with Fungotill Liposomal.
If you have experienced renal failure and are on dialysis, your doctor may start treatment with Fungotill Liposomal at the end of the dialysis procedure.

If you have any questions about the use of this medicine, please consult your doctor, pharmacist, or nurse.

Use in children and adolescents
This medicine is indicated for the treatment of children from 1 month to 18 years of age. The dose is individual and based on body weight, as in adults.
Fungotill Liposomal is not recommended for neonates under 1 month of age.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Side effects during infusion

Side effects may occur during the infusion:

• Very common (may affect more than 1 in 10 people): fever, chills, and tremors.
• Less frequent infusion-related side effects include: sensation of chest tightness, chest pain, shortness of breath, breathing difficulties (possibly with wheezing), hot flushes, faster than normal heartbeat, low blood pressure, and musculoskeletal pain (described as joint, back, or bone pain).

These side effects resolve rapidly when the infusion is stopped. Such reactions may not occur during future infusions of Fungotill Liposomal, or if the infusion is administered more slowly (over more than 2 hours). Your doctor may give you other medicines to prevent infusion-related reactions or to treat their symptoms if they occur. In case of a severe infusion-related reaction, your doctor will stop the Fungotill Liposomal infusion, and you must not receive this treatment again in the future.

Very common (may affect more than 1 in 10 people):

• low potassium levels in the blood, which may cause fatigue, confusion, muscle weakness, or cramps;
• nausea or vomiting;
• fever, chills, or tremors.

Common (may affect up to 1 in 10 people):

• low levels of magnesium, calcium, or sodium in the blood, which may cause fatigue, confusion, muscle weakness, or cramps;
• high blood sugar levels;
• headache;
• faster than normal heart rate;
• dilation of blood vessels, causing low blood pressure and hot flushes;
• shortness of breath;
• diarrhea;
• stomach (abdominal) pain;
• rash;
• chest pain;
• back pain;
• abnormal liver or kidney function test results detected in blood or urine tests;
• high potassium levels in the blood.

Uncommon (may affect up to 1 in 100 people):

• skin bleeding, unusual bruising, and prolonged bleeding after injury;
• severe allergic reaction (anaphylactoid);
• seizures or convulsions;
• breathing difficulties, possibly with wheezing.

Other side effects:
Not known (frequency cannot be estimated from available data):

• anaemia (low red blood cell levels), with symptoms of excessive tiredness, shortness of breath after mild exertion, and pale appearance;
• severe allergic reactions (anaphylactic) or hypersensitivity reactions;
• heart attacks and changes in heart rhythm;
• kidney failure and kidney problems. Symptoms include fatigue and reduced urine output;
• severe swelling of the skin around lips, eyes, or tongue;
• rhabdomyolysis (muscle breakdown);
• bone and joint pain.

Interference with blood phosphate test results: Falsely elevated phosphate levels in the blood may occur when blood samples from patients receiving Fungotill Liposomal are analyzed using a specific assay called PHOSm. If test results show high phosphate levels, further testing using a different method may be required to confirm the results.

Reporting of side effects

If you experience any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Fungotill Liposomal

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton after "Exp.". The expiry date refers to the last day of that month.
Store below 25°C.

In-use stability after reconstitution/dilution
Since Fungotill Liposomal does not contain any bacteriostatic agent, from a microbiological point of view, the reconstituted or diluted medicinal product should be used immediately.
The storage times and conditions during use prior to administration are the responsibility of the user and normally do not exceed 24 hours at 2–8 °C, unless reconstitution has been carried out under controlled and validated aseptic conditions.

However, the following chemical and physical in-use stability data have been demonstrated for Fungotill Liposomal:

In-use stability after reconstitution
Glass vials: 48 hours at 25 ± 2 °C exposed to ambient light.
Glass vials and polypropylene syringes: up to 7 days at 2–8 °C.
Do not freeze.
DO NOT STORE partially used vials for future patient use.

In-use stability after dilution with injectable dextrose solution
PVC infusion bag: 25 ± 2 °C or 2–8 °C. Do not freeze.

See the table below for recommendations:

Polyolefin infusion bags: 25 ± 2 °C or 2 - 8 °C. Do not freeze.
See the table below for recommendations:

Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of
medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Fungotill Liposomal contains
The active substance is amphotericin B. Each vial contains 50 mg of amphotericin B in liposomes (small
fat particles). After reconstitution, 1 mL of concentrate contains 4 mg of amphotericin B.
The other ingredients are hydrogenated soybean phosphatidylcholine, cholesterol, distearoylphosphatidylglycerol, All- rac-
α -tocopherol, sucrose (sugar), disodium succinate hexahydrate, sodium hydroxide (for pH adjustment) and concentrated hydrochloric acid (37%) (for pH adjustment).
Description of the appearance of Fungotill Liposomal and the contents of the pack
Fungotill Liposomal is a sterile, yellow lyophilized powder for concentrate for dispersion for infusion.
It is supplied in 20 mL clear glass vials (type I).
The closure consists of a rubber stopper and an aluminum seal with a removable blue plastic cap. Single-use vials are available in cartons with 5-micron filters.
Pack sizes: 1 vial with 1 filter and 10 vials with 10 filters.
Not all pack sizes may be marketed.
Marketing Authorization Holder
Tillomed Italia S.r.l.
Viale Giulio Richard 1, Torre A
20143 Milan, Italy
Manufacturer
Tillomed Malta Limited
Malta Life Sciences Park,
LS2.01.06 Industrial Estate,
San Gwann, SGN 3000,
Malta
SGS Pharma Magyarorszag Kft.
Derkovits Gyula Utca 53,
Budapest XIX, 1193,
Hungary

The following information is intended exclusively for healthcare professionals:

READ THE ENTIRE SECTION AND THE PRODUCT CHARACTERISTICS SUMMARY CAREFULLY BEFORE BEGINNING RECONSTITUTION
Due to its unique pharmacokinetic properties, the product is not equivalent to non-liposomal formulations of amphotericin B.
Fungotill Liposomal must be reconstituted using sterile water for injections (without bacteriostatic agent) and diluted exclusively in dextrose infusion solution 50 mg/mL (5%), 100 mg/mL (10%) or 200 mg/mL (20%).
The use of solutions other than those recommended, or the presence of a bacteriostatic agent (e.g. benzyl alcohol) in the solution, may cause precipitation of Fungotill Liposomal.
Fungotill Liposomal is NOT compatible with sodium chloride solution and must not be reconstituted or diluted with sodium chloride solution, nor administered through an intravenous line previously used for saline solution, unless it is first flushed with a dextrose infusion solution 50 mg/mL (5%), 100 mg/mL (10%) or 200 mg/mL (20%). If this is not feasible, Fungotill Liposomal must be administered through a separate line.
DO NOT mix Fungotill Liposomal with other medicinal products or electrolytes.
Strict aseptic technique must be observed during all manipulations, as Fungotill Liposomal and the materials specified for reconstitution and dilution do not contain preservatives or bacteriostatic agents.
Fungotill Liposomal must be reconstituted by appropriately trained personnel.
The vials of Fungotill Liposomal containing 50 mg of amphotericin B are to be prepared as follows:

1. Add 12 mL of sterile water for injections to each vial of Fungotill Liposomal, to obtain a preparation containing 4 mg/mL of amphotericin B.

2. IMMEDIATELY after adding water, SHAKE THE VIAL VIGOROUSLY for 30 SECONDS to completely disperse Fungotill liposomal. After reconstitution, the concentrate is a translucent yellow dispersion. Visually inspect the vial for particles and continue shaking until complete dispersion is achieved, but not exceeding 120 seconds. Do not use if precipitation or foreign matter is present.

3. Calculate the volume of reconstituted Fungotill Liposomal (4 mg/mL) to be further diluted.
4. The ready-to-use infusion dispersion is obtained by diluting the reconstituted Fungotill Liposomal with 1–19 volumes of dextrose infusion solution 50 mg/mL (5%), 100 mg/mL (10%) or 200 mg/mL (20%). The final concentration will thus fall within the recommended range of 2.0 – 0.2 mg/mL of Amphotericin B as Fungotill Liposomal.
5. Withdraw the calculated volume of reconstituted Fungotill Liposomal into a sterile syringe. Using the provided 5-micron filter, instill the Fungotill Liposomal preparation into a sterile container containing the correct amount of dextrose infusion solution 50 mg/mL (5%), 100 mg/mL (10%) or 200 mg/mL (20%).

A membrane in-line filter may be used for intravenous infusion of Fungotill Liposomal.
However, the average pore diameter of the filter must not be less than 1.0 micron.
DO NOT store opened vials for future use.
Since Fungotill Liposomal does not contain antibacterial agents, from a microbiological standpoint, the reconstituted or diluted medicinal product should be used immediately.
The user is responsible for the duration and storage conditions of the ready-to-use solution prior to administration. Under normal circumstances, storage should not exceed 24 hours at 2–8 °C, unless the product has been prepared under controlled and validated aseptic conditions.
The medicinal product is for single use only, and any unused solution must be discarded. Do not store opened vials for future use.
Any unused medicinal product or waste material must be disposed of in accordance with applicable local regulations.